The mechanism of adhesion formation represents a variation of the physiological healing process wherein vital tissues, usually different tissues, adhere to one another in an undesirable fashion. See, for example, Pados et al., 1992, Current Opinion in Obstetrics and Gynecology, 4:412-18.
For example, increased permeability of blood vessels as a result of a peritoneal injury produces a serosanguinous, proteinaceous exudate that quickly coagulates, forming a fibrinous material that first plugs the defective area, and which is further infiltrated by inflammatory cells. If this fibrinous mass is not dispersed by fibrinolysis, fibroblasts and blood vessels invade, resulting in organization and formation of adhesions.
Pelvic or abdominal adhesions, a frequent occurrence after abdominal surgery and inflammatory processes such as infections and endometriosis, represent a major cause of female infertility. Such adhesions further increase intra-operative complications, constitute a major cause of small bowel obstructions, and have been implicated in the pathogenesis of chronic pelvic pain.
Vital tissues, such as blood vessels or organs including the kidney, liver, and intestines, are coated with mucous membranes or serous membranes so that they can function independently of each other. Surgical operations or inflammation in those portions of the body coated with serous membranes could result in adhesion between these and adjacent tissues.
In the field of orthopedics, acute or chronic arthritis such as suppurative, gonorrheal, tuberculous or rheumatoid arthritis, or traumatic injuries at a joint (such as fractures or sprains) would result in ankylotic diseases wherein the surface of the bones constituting the joint adhere to each other and thereby restrict the mobility of the joint. Congenital radioulnar synostosis, wherein the radius and ulna adhere together, is difficult to remedy by a surgical operation, as the separated bones would frequently re-adhere.
When neural spine and spinal cord are removed dorsally by a surgical operation in a vertebral canal cavity in treating myeloma, intervertebral hemia, or adhesive spinal meningitis, it is necessary to prevent adhesion to the body wall.
Suturing of ruptured tendons and tendon transfer would sometimes fail because of the post-operative adhesion of the tendon to the scar in the skin. Furthermore, in the case of rupture of a flexor tendon between a metacarpophalangeal joint and a proximophalangeal joint, the function of the finger would not recover by the intermittent suture of musculus flexor digitorum superficialis and musculus flexor digitorum profundus, as these tendons, if injured simultaneously, would adhere to one other. Therefore, is also necessary to prevent adhesion between the two tendons in this case.
In the field of thoracosurgery, bronchi dilated by primary diseases, such as pulmonary or suppurative diseases, would allow the extension of inflammation over the surrounding pulmonary parenchyma and the formation of a suppurative focus, thereby resulting in adhesion to the pleura. In addition, lung cancer would result in adhesion to the body wall.
In the field of abdosurgery, external damages, such as disjunction or rupture by a severe impact, or morbid damages such as inflammation or tumor in organs in an abdominal cavity, including liver, kidney, pancreas, spleen and intestine, would result in adhesion of organs to each other or of an organ to the abdominal wall. Rupture of the diaphragm or peritoneum caused by severe external closed damage would result in adhesion of an organ to the abdominal wall. Further, ileus of the small or large intestine, which has the same meaning as intestinal obstruction and generally refers to an acute obstruction, would be mainly caused by adhesive ileus, wherein the intestinal cavity is closed by a crooked or flexed intestinal tract resulting from adhesion in the abdominal cavity, most of which would be formed post-operatively. Therefore, it is necessary to prevent adhesion in the abdominal cavity after the operation to prevent said adhesive ileus. Abdominal abscess could sometimes result in adhesion of peritoneum, diaphragm, or pleura to each other. In addition, adhesion between adjacent organs, or of an organ to the abdominal wall, should be prevented in the case of various diseases or tumors which cannot be removed completely in internal organs.
In the field of obstetrics and gynecology, endometritis, excessive artificial abortions, or intra-uterine curettage would sometimes result in partial or whole adhesion of the placenta to the uterine wall, making separation of the placenta at delivery difficult. Adhesion formation following infertility surgery, such as microsurgery, reconstructive tubal surgery, laparotomy and laparoscopy, remains a significant cause for failure of conception. For example, adhesions which encapsulate the ovary or the distal oviduct, or which distort the normal relationship that exists between the ovary and the oviduct, may interfere with fertility by preventing or impeding ovum pick-up. See, for example, Gomel et al., 1992, Current Opinion in Obstetrics and Gynecology, 4:390-99. Furthermore, cancerous tissues found in breast cancer multiply remarkably and may adhere to adjacent skin or a tendon.
In the field of brain surgery, adhesive arachnitis would be induced by chronic or suppurative intracranial inflammation (resulting from an unknown primary cause, syphilis, tuberculosis, or the like), intrathecal injection of medicine in therapy, or myelography.
In addition, adhesions resulting from facial palsy caused by a malignant tumor in the salivary gland would sometimes restrict mobility. A cancerous cervical lymph node adheres to the surrounding tissues to thereby restrict mobility.
In the field of ophthalmology, ocular surgery involving the musculature, ligaments, glands, and nerve tissue may generate post-operative adhesions.
Similarly, periodontal surgery may result in post-operative adhesions between soft and hard tissues of the mouth and throat, such as the palate, gums, teeth, and bone (such as the jawbone).
As described above, adhesion of vital tissues, large or small, may be observed in most of the surgical fields. Adhesion formation may occur for various reasons, including mechanical and chemical stimulation of vital tissues accompanying surgical operations, post-operative bacterial infection, inflammation, or complications. Additional factors, such as foreign body reactions, hemorrhages, and endometriosis may influence adhesion formation.
It is thus desirable to prevent the formation of adhesions, particular post-operative adhesions. A number of preventative methods have been developed. Effective adjuvants for the prevention or reduction of post-operative adhesions continue to elude the surgeon, and new substances are being experimented with.
Initially, drugs or adhesion-inhibiting agents, such as steroids, polyvinyl-pyrrolidone (PVP), chondroitin sulfuric acid, or an aqueous solution of sodium alginate, were administered, usually at the wound site, to minimize adhesion formation. For example, the efficacy of hyaluronic acid solution on postoperative adhesion formation in rat models has been found to be minimal (see Urman et al., 1991, Fertil. Steril., 56:568-70). However, success was limited, as the effects were neither constant nor perfect. Additionally, water-soluble adhesion-preventing agents may enter normal regions entirely irrelevant to the operation, thereby possibly causing, rather than preventing, adhesion. Additionally, use of fibrinolytic agents, anti-coagulants, anti-inflammatory agents, and antibiotics has been attempted with limited success.
Early methods for mechanical separation of tissues included the use of materials such as dextran, mineral oil, silicone, providine, vaseline, crystalloid solutions, and carboxymethylcellulose.
Physical barriers mechanically separate the opposed surfaces and exert their protective action, at least partly, because they remain in place beyond a crucial point (often, about 3 days), at which time competition of fibrinolytic activity and fibrosis will determine the formation of adhesions. Physical barriers, including those of endogenous tissue (such as omental grafts, peritoneal grafts, bladder strips, and fetal membranes such as amniotic membranes), and exogenous material (such as oxidized cellulose, oxidized regenerated cellulose, gelatin, rubber sheets, metal foils, and plastic hoods) have long been used, but with little success.
Non-resorbable membranes, such as Goretex.RTM. (PTFE; polytetrafluoroethylene) sheets or membranes, Silastic.RTM. (a medical grade silicone elastomer produced by Dow Corning), and Millipore.RTM. filter barriers, are advantageous in that they remain intact long after implantation and thus play the role of barrier perfectly, but are disadvantageous in that they require two surgical interventions: first to apply the membrane (using sutures or adhesives), and second to remove the membrane 4 to 6 weeks after the initial surgery.
Artificial biodegradable (e.g., resorbable) membranes, such as Gelfoam.RTM. (an absorbable collagen foam or sponge produced by Upjohn), have also been used. Terao et al. (European Patent Application No. 431479, published 12 Jun. 1991 ) describe a collagen-chitin membrane for wound-covering and adhesion prevention. Although such resorbable materials alleviate the need for a second surgical intervention, they are less than perfect in view of undesirably rapid rates of resorption and the often substantial concomitant inflammatory response.
The anti-adhesion properties of fibrin glue (produced by Tisseel, Canada) were examined and found to yield results similar to those observed for sutures (see Tulandi, 1991, Fertil. Steril., 56: 136-38). An alternative material, Vicryl.RTM. (polygalactin-910), is a slowly resorbable, biocompatible, tightly woven mesh graft which has been used as a dural substitute in neural surgery (see Fleisher et al., 1987, J. Dent. Res. 66 (Spec. Issue Mar.), Vol. 281, Abstract 1393). Both Interceed.RTM. and Surgicel.RTM. (produced by Johnson & Johnson), fabrics composed of oxidized regenerated cellulose (the former includes the anticoagulant, heparin), have been studied in connection with adhesion formation in a rat uterine horn model (see Pagidas et al., 1992, Fertil. Steril., 57:933-38). Poloxamer 407.RTM. (produced by Mediventures, Inc.) is representative of a group of polymers which exist as liquids at room temperature, but which form a solid gel at body temperature. Such materials have been shown to have anti-adhesion properties in rats (for pelvic wounds) and rabbits (see Steinleitner et al., 1991, Obstet. Gynecol., 77:48-52).
One key disadvantage of the physical barriers currently available involves the method of attachment. In order to prevent the formation of adhesions, anti-adhesive adjuvants must remain in place for a required period of time. As the tissues to be separated are often somewhat mobile, especially relative to adjacent or overlying tissue (for example, abdominal linings, abdominal organs, tendons, and the like), it is necessary to ensure that the adjuvant remains both intact and in place. Methods of attachment, such as suturing (for example, with microsutures) and biocompatible adhesive glues have been used, but with limited success. The attachment of sutures themselves (for example, by stitching) causes surgical trauma and additional potential for adhesion formation. In addition, sutures and adhesives often provide imperfect attachment, and the adjuvant tears, rips, or is otherwise freed from the attachment points, and is thereby unable to perform an anti-adhesion function.
It is therefore an object of the invention to provide compositions and methods for preventing the formation of adhesions. It is another object of the invention to provide new adhesion preventatives which are resorbable and which therefore do not require surgical intervention for removal. It is yet another object of the invention to provide adhesion preventatives, in the form of anti-adhesion-films, which reduce or remove the need for mechanical means, such as sutures or adhesive tape, for attachment or to ensure immobility. It is still another object of the present invention to provide new anti-adhesion films which have, in combination with anti-adhesion properties, wound-healing and hemostasis-preventative functions.